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W O 2009/100159 A3 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization IN International Bureau (10) International Publication Number (43) International Publication Date 13 August 2009 (13.08.2009) PCT W O 2009/100159 A3 (51) International Patent Classification: (74) Agents: HOFFMANN, David, C. et al.; Morrison & Fo C12Q 1/68 (2006.01) C07H 21/00 (2006.01) erster LLP, 755 Page Mill Road, Palo Alto, CA C12N15/11 (2006.01) A61K 48/00 (2006.01) 94304-1018 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US2009/033117 kind of nationalprotection available>: A, AG, AL, AM, BY, BZ, (22) International Filing Date:AT, AU, AZ, BA, BB, BG, , BR, BW, CA, N , C O , CR , C U , CZ , D E, D K , D M , D O , D Z , 4 In er a io4 a209Feruay Fiin 04.2.209)Date: EC, EE,C H , EG,C ES, Fl, GB, GD, GE, GH, GM, GT, FIN, (25) Filing Language: English HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (26) Publication Language: English MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, (30) Priority Data: NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, 61/026,077 4 February 2008 (04.02.2008) US SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant (for all designated States except US): BIPAR SCIENCES, INC. [US/US]; 400 Oyster Point Boulevard, (84) Designated States (unless otherwise indicated, for every Suite 200, South San Francisco, CA 94080 (US). kind of regionalprotection available>: ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (72) Inventors; and ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, (75) Inventors/Applicants (for US only): OSSOVSKAYA, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, Valeria S. [US/US]; 96 Toledo Way, #304, San Francis- ES, Fl, FR, GB, GR, HR, HU, 1E, IS, IT, LT, LU, LV, _ co, California 94123 (US). SHERMAN, Barry M. [US/ MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), US]; 2830 Churchill Drive, Hillsborough, California OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, - 94010 (US). MR, NE, SN, TD, TG). - [Continued on next page] (54) Title: METHODS OF DIAGNOSING AND TREATING PARP-MEDIATED DISEASES (57) Abstract: Disclosed are methods of identifying a disease treat able with modulators of differentially expressed genes in a disease, -Figure 1 including atECOENG least PARP modulators,S FGGG, by identifyingH the Mlevel T ofex N pressing of differentiallyHR0U D expressedL N S genes,P includingE G Mat leastN PARP,P Rin KZ0A C K R S T U Y A D E a plurality of samples from a population, making a decision regarding - 01 Collect a sample from a subject suffering identifying MGCKthe disease treatableN W by Xmodulators Y Z to theA differentiallyG I O -from a disease expressed genes wherein the decision is made based on the level of I expression of the differentially expressed genes. The method can fur I ther comprise treating the disease in a subject population with modu I lators of identified differentially expressed genes. The methods relate Identiy if the disease is to identifying up-regulated expression of identified differentially-ex a0PAPmediated pressed genes in a disease and making a decision regarding the treat - 02 disease treatable by ment of the disease. The level of expression of the differentially ex PARP inhibitor pressed genes in a disease can also help in determining the efficacy of Identify an up- the treatment with modulators to the differentially expressed genes. 103 regulated level of PARP in the sample Identify if other genes 104 are differentially exprssed in the Prsample Treatment of the disease with PARP O105 inhibitor alone or in O combination W O 20 0 9 /10 0 15 9 A3 ||1llll|||1ll|| 111||||||||||||||||||||||||||||||||||||||||I|||||||||||||||||||1 Published: (88) Date of publication of the international search report: - with internationalsearch report (Art. 21(3)) 29 October 2009 - before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) WO 2009/100159 PCT/US2009/033117 METHODS OF DIAGNOSING AND TREATING PARP-MEDIATED DISEASES CROSS REFERENCE TO RELATED APPLICATIONS [00011 This application claims the benefit of U.S. Provisional Application No. 61/026,077, entitled, "Methods of Diagnosing and Treating PARP-Mediated Diseases," filed February 4, 2008, which is 5 incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION [0002] The etiology of cancer and other diseases involves complex interactions between cellular factors, including cellular enzymatic receptors and other downstream intracellular factors that relay signals through the intracellular signaling network. Growth factor receptors have been recognized as a key factor in cancer 10 biology, playing a significant role in the progression and maintenance of the malignant phenotype (Jones et al., 2006, Endocrine-Rel. Cancer, 13:545-551). For example, the expression of Epidermal Growth Factor Receptor (EGFR), a tyrosine kinase receptor, has been implicated as necessary in the development of adenomas and carcinomas in intestinal tumors, and subsequent expansion of initiated tumors (Roberts et al., 2002, PNAS, 99:1521-1526). Overexpression of EGFR also plays a role in neoplasia, especially in tumors of 15 epithelial origin (Kari et al., 2003, Cancer Res., 63:1-5). EGFR is a member of the ErbB family of receptors, which includes HER2c/neu, Her2 and Her3 receptor tyrosine kinases. The molecular signaling pathway of EGFR activation has been mapped through experimental and computer modeling, involving over 200 reactions and 300 chemical species interactions (see Oda et al., Epub 2005, Mol. Sys. Biol., 1:2005.0010). [00031 Another critical cellular pathway that is overexpressed by tumors, including mediation of the 20 proliferation of cancer cells, is the insulin-like growth factor (IGF) signaling pathway (Khandwala et al., 2000, Endo. Rev., 21:215-244; Moschos and Mantzoros, 2002, Oncology 63:317-332; Bohula et al., 2003, Anticancer Drugs, 14:669-682). The signaling involves the function of two ligands, IGFI and IGF2, three cell surface receptors, at least six high affinity binding proteins and binding protein protease (Basearga et al., 2006, Endocrine-Rel. Cancer, 13:S33-S43; Pollak et al., 2004, Nature Rev. Cancer 4:505-518). The insulin 25 like growth factor receptor (IGF1R) is a transmembrane receptor tyrosine kinase that mediates IGF biological activity and signaling through several critical cellular molecular networks including RASORAF ERK and P13-AKT-mTOR pathways. A functional IGFIR is required for transformation, and has been shown to promote tumor cell growth and survival (Riedemann and Macaulay, 2006, Endocr. Relat. Cancer, 13:533-43). Several genes that have been shown to promote cell proliferation in response to IGF-l/IGF-2 30 binding in the IGFlR pathway include Shc, IRS, Grb2, SOS, Ras, Raf, MEK and ERK. Genes that have been implicated in the cell proliferation, motility and survival functions of IGFl R signaling include IRS, P13-K, PIP2, PTEN, PTP-2, PDK and Akt. [0004] The signaling interplay between IGF signaling, IGFl receptor and EGFR is important in the regulation of EGFR-mediated-pathway, and can contribute to a resistance to EGFR antagonist therapy 35 (Jones et al., 2006, Endocrine-Rel. Cancer, 13:845-851). [00051 Another pathway that is of interest in the proliferation and control of cancer growth and development includes the Eta family of transcription factors. The Ets family domain proteins, which are defined on the basis of a conserved primary sequence of their DNA-binding domains, function as either -1 WSGR Docket No. 28825.750.601 WO 2009/100159 PCT/US2009/033117 transcriptional activators or repressors, and their activities are often regulated by signal transduction pathways, including MAP kinase pathways (Sharrocks, et at., 1997, Int. J. Biochem. Cell Biol. 29:1371 1387). ETS transcription factors, such as ETS1, regulate numerous genes and are involved in stem cell development, cell senescence and death, and tumorigenesis. The conserved ETS domain within these 5 proteins is a winged helix-turn-helix DNA-binding domain that recognizes the core consensus DNA sequence GGAA/T of target genes (Dwyer et at., 2007, Ann. New York Acad. Sci. 1114:36-47). There is a growing body of evidence that Ets 1 protein has oncogenic potential by playing a key role in the acquisition of invasive behavior of a tumorigenic cell. Among the genes that belong to the Ets 1 pathway to carry out its tumorigenic functions include the matrix metalloproteases MMP-1, MMP-3, MMP-9, as well as urokinase 10 type plasminogen activator (uPA) (Sementchenko and Watson, 2000, Oncogene, 19:6533-6548). These proteases are known to be involved in extracellular matrix (ECM) degradation, a key event in invasion. In angiosarcoma of the skin, Eta 1 is co-expressed with MMP-1 (Naito et al., 2000, Pathol. Res. Pract. 196:103 109). Ovarian carcinoma cells and stromal fibroblasts in breast and ovarian cancer produce MMP-1 and MMP-9 along with Ets 1 (Behrens et al., 2001, 1. Pathol. 194:43-50; Behrens et al., 2001, Int. J. Mol. Med. 15 8:149-154). In lung and brain tumors, Ets expression correlates with uPA expression (Kitange et al., 1999, Lab. Invest. 79:407-416; Takanami et al., 2001, Tumour Biol. 22:205-210; Nakada et al., 1999, J. Neuropathol. Exp. Neurol. 58:329-334). When overexpressed in endothelial cells or hepatoma cells, Ets 1 was shown to induce the production of MMP-l, MMP-3 plus MMP-9, or MMP-1, MMP-9 plus uPA, respectively (Oda et al., 1999, J.
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